Genetic Alterations In Proliferative Breast Disease
Sunil R. Lakhani
Institute of Cancer Research
The development of modern molecular genetic techniques has allowed breast cancer researchers to
clarify the multistep model for breast carcinogenesis. Laser capture microdissection combined with
comparative genomic hybridisation and/or LOH methods have confirmed that many preinvasive lesions of the
breast harbour chromosomal abnormalities at loci known to be altered in invasive breast carcinomas. The
current data do not provide strong evidence for ductal hyperplasia of usual type as a precursor lesion
but atypical hyperplsia and in situ carcinoma appear to be non-obligate
precursors. In the lecture, I review the current knowledge and the contribution of molecular genetics in
the understanding of breast cancer precursors and preinvasive lesions.
Ductal Carcinoma in situ (DCIS)
The analysis of genetic alterations in DCIS has provided new insights in the biology of these lesions.
As with invasive carcinoma, abnormalities of chromosomes 1 and 16 have been identified in some of these
cases.1 The comparative genomic hybridisation (CGH) method has been modified for paraffin-embedded
material and this has allowed studies on archival material and in particular, the study of preinvasive
disease.2-8 CGH analysis of DCIS has demonstrated a large number of alterations including gains of
1q, 5p, 6q, 8q, 17q, 19q, 20p, 20q, and Xq and losses of 2q, 5q, 6q, 8p, 9p, 11q, 13q, 14q, 16q, 17p, and
22q.2-8 These alterations are similar to that identified in invasive carcinoma, adding weight to the
idea that DCIS is a precursor lesion. Recently, it has been demonstrated that different types of DCIS
show different genetic alterations; hence there may be multiple pathways for the evolution of DCIS.4,6,8,9
Alterations at 16q are much more frequent in low grade DCIS compared to high grade DCIS, in
which alterations at 13q, 17q, and 20q are seen more often.4,6,7,10 Similar findings in invasive
carcinomas of low and high grade also support the idea that low grade and high grade lesions develop by
separate pathways rather than by de-differentiation.4,6,7,10 With the use of microdissection
techniques to isolate small microscopic lesions, loss of heterozygosity (LOH) has also been investigated
in preinvasive disease.11-17 O'Connell et al11 have carried out studies on preinvasive lesions
using a variety of chromosomal markers and showed that 50% of the proliferative lesions and 80% of the
DCIS shared their LOH patterns with invasive carcinoma. Stratton et al12 studied cases of DCIS
associated with invasive carcinoma and cases of 'pure' DCIS without an invasive component using a limited
set of microsatellite markers on chromosomes 7q, 16q, 17p and 17q. The study demonstrated a similar
frequency of LOH in both subsets of DCIS to invasive carcinoma providing further strong evidence that
DCIS is likely to be a precursor of invasive carcinoma. There is considerable support for these early
data from a number of other laboratories.13-20 CerbB2 protein has been
identified in a high proportion (60-80%) of DCIS of high nuclear grade (HNG)-comedo-type but is not
common in the low nuclear grade (LNG) forms. Allred et al21 have shown that the expression is higher
in invasive carcinoma associated with DCIS compared to those without DCIS. It is very rarely expressed
in LCIS.22 This gene product has not been identified in benign proliferative disease or ADH.23 The
data suggest that CerbB2 is important in the transition from a 'benign' to
'malignant' phenotype. The different frequency of expression in in situ and
invasive carcinoma is a mystery. Either expression is switched off during invasion or many CerbB2 positive DCIS do not transform to invasive malignancy. p53 protein
expression has been demonstrated using immunohistochemistry in HNG-DCIS (comedo type).24 The
mechanism may be gene mutation but this has only been confirmed in some cases. Like CerbB2, p53 protein expression is rare in LCIS and has not been demonstrated in
atypical ductal hyperplasia or other benign proliferative disease.25 Done et al26 demonstrated
that p53 mutations found in DCIS and associated invasive cancer were absent from benign proliferative
lesions from the same breast. Overall, there is a considerable body of evidence indicating that DCIS,
particularly of high grade, shares many molecular genetic alterations with invasive carcinoma and hence
is a direct precursor of invasive carcinoma.4-8,14,15 Moreover, gain of chromosome 1q and loss of 16q
which are highly prevalent in low grade DCIS, are frequently found in tubular carcinoma, tubulo-lobular,
lobular, and grade 1 invasive ductal carcinomas.4,6,8,27
Lobular Carcinoma in situ (LCIS)
Lobular carcinoma in situ of the breast is an uncommon lesion and is
composed of discohesive cells with small monomorphic hyperchromatic nuclei. It is usually an incidental
finding and is not visible on mammography.28 The majority of the cases are diagnosed between 40-50
years of age, a decade earlier than DCIS. It is also multifocal and bilateral in a high proportion of
cases.28 Approximately one fifth of the cases will progress to invasive cancer over a 20-25 year
follow up period.28 Although invasive ductal carcinomas, specially of tubular type, do occur after
LCIS, most cases associated with LCIS are ILC.28 It has been said that the risk is equal in both
breasts,29 however, there are data to suggest that the risk is skewed in favour of the ipsilateral
breast.28,30 Despite this, the features of LCIS have raised questions about the biological nature and
it is still generally considered to be "a marker of increased risk" rather than a true precursor of
invasive carcinoma. In our laboratories, we have carried out CGH analysis on LCIS and atypical lobular
hyperplasia (ALH).31 Loss of material from 16p, 16q, 17p and 22q and gain of material from 6q were
found at a similar high frequency in both LCIS and ALH. Losses at 1q, 16q, and 17p are also seen in
invasive lobular carcinomas.8,32 LOH data in LCIS are also limited but do demonstrate a similarity
between LCIS & ILC.33,34 E-Cadherin is a candidate tumour suppressor gene on 16q22.1, which is
involved in cell-cell adhesion and in cell cycle regulation through b–catenin/Wnt pathway.35 The
majority of invasive ductal carcinoma-NST has been shown to exhibit positive staining by
immunohistochemistry while most invasive lobular carcinomas are negative.36 Berx et al37
identified protein truncation mutations in 4/7 invasive lobular carcinomas but failed to identify any
changes in 42 invasive ductal carcinoma-NST or medullary carcinomas. The mutations in the lobular
tumours were accompanied by LOH in the region of the gene and absent staining by immunohistochemistry.
E-Cadherin staining has also been identified in DCIS and the molecule is expressed in normal
epithelium but staining is rarely seen in LCIS.38-43 Recently, some authors have advocated the use of
E-cadherin as an adjunct antibody in the differentiation of LCIS from DCIS.40-43 In addition, Vos et
al44 have demonstrated the same truncating mutation in the E-Cadherin gene in LCIS and the adjacent
invasive lobular carcinoma. The data provide strong evidence for the role of E-Cadherin gene in the
pathogenesis of lobular lesions as well as supporting the hypothesis for a precursor role for LCIS.
Although E-cadherin germline mutation has been demonstrated in diffuse gastric carcinoma, there is only a
single case of lobular carcinoma with germline alteration in the gene.35
Atypical Ductal Hyperplasia (ADH)
ADH is a controversial lesion, which shares some but not all features of DCIS. It poses considerable
difficulties in surgical histopathology. In order to address this problem, Page & Rogers45 laid
down criteria for the diagnosis of this entity. Rosai46 in his study had demonstrated a high
inter-observer variability in the diagnosis of ADH, however, a subsequent study by Schnitt et al,47 in
which the pathologist used the Page criteria showed an improvement with complete agreement in 58% of
cases. Within the UK National Quality Assurance Scheme,48 agreement even amongst experienced breast
pathologists has been low. Lakhani et al49 demonstrated that LOH identified at loci on 16q and 17p in
invasive carcinoma and DCIS is also present in ADH with a similar frequency. O'Connell et al13
studied 51 cases of ADH at 15 polymorphic loci and found LOH at at least one marker in 42% of the cases.
The studies demonstrate that morphological overlaps are reflected at the molecular level and raise
questions about the validity of separating ADH from DCIS. CGH analysis of 9 cases of ADH revealed
chromosomal abnormalities in 5 of them.50 As expected, owing to the morphological overlap with low
grade DCIS, losses of 16q and 17p were the most frequent changes found in ADH.50
Hyperplasia of Usual Type (HUT)
O'Connell et al13 have demonstrated that LOH at many different loci can be identified in HUT with
frequencies ranging from 0-15%. These figures are similar to those of Lakhani et al51 who reported
data in non-atypical hyperplasia (HUT) dissected from benign breast biopsies. LOH was identified at
frequencies ranging from 0% to 13% at locus on 17q. These frequencies are much lower than those
identified in DCIS and ADH (range 25-55%). Wasington et al published similar results.52 In their
series,50 4 of 21 HUTs showed LOH in one to five loci. LOH at 16q (3 cases), 9p (3 cases), and 13q (2
cases) were the most frequent findings.50 Although CGH analysis of HUTs has demonstrated that the
majority of these lesions harbour no chromosomal abnormalities,6,50 the picture dramatically changes
when they are associated with ADH or DCIS,50 In this setting, most lesions show losses of 16q and 17p.50
However, it is still premature to accept HUT as a precursor of DCIS and IDC, because in those
cases associate with ADH or DCIS, the studies published so far could not exclude the presence of true
malignant cells admixed with 'benign' hyperplastic cells of HUTs.
Columnar cell lesions
Columnar cell lesions have been a major source of confusion among breast pathologists,
first because they have been reported under several different names, including columnar alteration of
lobules, blunt duct adenosis, metaplasie cylindrique, cancerization of small
ectatic ducts of the breast by ductal carcinoma in situ cells with apocrine snouts,53 columnar
alteration with prominent apical snouts and secretions,54 and clinging carcinoma in situ.55 These lesions represent a spectrum that ranges from columnar cell
alteration in luminal cells to ADH and flat/cliniging DCIS. Regardless of the fact that there are
several lines of evidence showing an association with tubular carcinoma,54,55 only one paper addressed
the genetic abnormalities in these lesions.55 Moinfar et al55 demonstrated that 77% of columnar
cell lesions (either with or without atypia) harbour chromosomal abnormalities at least in 1 locus and
the most frequent loci of LOH were 11q21-23.2, 16q23.1-24.2, and 3p14.2.55 Noteworthy, 16q and 11q
are frequently lost in tubular carcinomas.27,55 More interestingly, these authors55 have also
shown that otherwise luminal cells with mild nuclear atypia lining ducts at the vicinity of columnar cell
lesions may also have loss of genetic material in up to 6% of the cases.
Over the last few years, seven studies have also demonstrated that LOH identified in invasive
carcinoma is already present in morphological normal lobules.17,35,52,56,57,58,59 Lakhani et al58
have demonstrated that LOH identified in normal breast epithelial cells is seen independently in luminal
and myoepithelial cells, suggesting a common precursor cell for the two epithelial cells. Even more
thought provoking is the data published by Moinfar et al,17 who demonstrated the presence of
concurrent and independent genetic alterations in normal appearing stromal and epithelial cells located
either at the vicinity or at a distance from the foci of DCIS or IDC. The extent and frequency of
alterations and their significance in the multistep carcinogenesis remains unknown at present. It should
be noted that in breasts without malignant changes, genetic alterations in normal cells are rather
infrequent, subtle and fairly random;6 conversely, one paper has demonstrated that normal lobules and
adjacent in situ carcinomas show concordant genetic alterations,17 and
other suggested that LOH in normal breast terminal duct lobular units predicts for local recurrence.59
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